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A recent retrospective study (Clin Gastroenterol Hepatol 2018; 16: 68-74) compared adult patients who had ulcerative colitis (UC) with (n=23) and without primary sclerosing cholangitis (n=120) (PSC). All patients had pancolitis and were in clinical remission.

Key finding:

Patients with UC-PSC had more subclinical endoscopic activity (odds ratio (OR) 4.21) and histologic activity (OR 5.13) in the right colon compared with patients without PSC

It is known that the presence of PSC is a risk factor for colorectal cancer (CRC). A previous meta-analysis (RM Soetiknno et al. Gastrointest Endosc 2002; 56: 48-54) described a OR of CRC of 4.09.

My take: This study shows that UC patients with PSC who are in clinical remission have a greater degree of endoscopic and histologic inflammation in the proximal colon compared to patients without PSC. This increased inflammation is a likely factor in the increased risk for CRC.

In this study, the stool from either patients with CRC or control patients was gavaged into mice twice a week for 5 weeks. One group of mice had received azoxymethane (AOM) which induces neoplasia and the other group were germ-free mice. Extensive studies involving immunohistochemistry, expresssion microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry.

Key findings:

Conventional, AOM-treated mice who received gavage from patients with CRC had significantly higher proportions of high-grade dysplasia (P<.05) and macroscopic polyps (P<.01)

Among the germ-free mice fed with stool from patients with CRC, there was a higher proportion of proliferating Ki-67-positve cells

These findings correlated with more dysbiosis in the mice who received stool from patients with CRC and with upregulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, and invasiveness

“This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.”

My take: This study shows that microbiota clearly influence the risk of CRC. I infer from this study that this could explain the potential healthy roles of diets with more fruits and vegetables, that promote healthier microbiota as well as the potential detrimental role of diets with more processed meats.

The ability to measure drug levels has changed how we think about refractory medical disease, particularly in patients with inflammatory bowel disease. Prior to the availability of therapeutic drug monitoring (TDM), in some situations poor response to therapy could be ascribed to variability in host immune response. Now, it is clear that many cases of refractory medical disease are due to insufficient drug level. TDM allows for dose individualization to target the right amount of medication.

TDM has an accepted role in anti-TNF therapy. Now, a study (R Battat et al. Clin Gastroenterol Hepatol 2017; 15: 1427-34) extends the concept of TDM to ustekinumab. This study which took place between 2014-2015 examined ustekinumab use in 62 patients with refractory Crohn’s disease (CD). Ustekinumab dosing: 90 mg SC at weeks 0, 1, and 2 for induction, then 90 mg every 4 or 8 weeks for maintenance.

Key findings:

At week 26, 80.7% of patients had a clinical response, 66.1% had a clinical remission, and 58.9% had an endoscopic response.

In those with an endoscopic response, the mean trough concentration of ustekinumab was 4.7 mcg/mL compared with 3.8 mcg/mL those without an endoscopic response.

Using a trough threshold of 4.5 mcg/mL at week ≥26, 75.9% had an endoscopic response whereas those with a level below this trough had a 40.7% endoscopic response

The authors did not detect antibodies to ustekinumab in any patient. The authors note that ustekinumab has low immunogenicity and prior UNITI studies indicated antibody formation in 0.2% after induction and 2.3% at 1 year.

Unlike combination therapy with anti-TNF therapy, “concurrent immunosuppressive therapy does not explain low immunogenicity, as only 25.8% of patients received these and had neither improved clinical outcomes nor higher drug concentrations.”

Thus far, no clinical studies have demonstrated improved clinical outcomes with dose escalation in the setting of low ustekinumab levels. A prospective trial would be helpful.

My take: This study shows promising results for ustekinumab for refractory CD. The low immunogenicity indicates that monotherapy is likely appropriate. A target level of >4.5 mcg/mL indicates a higher likelihood of response.

A recent study (RS Mehta et al. Gastroenterol 2017; 152: 1944 & summarized in editorial, 1821-23) examined the effects of a “Western” diet and a “prudent” diet on the risk of colorectal cancer (CRC). Data was derived from two large prospective cohorts involving more than 137,000 participants for up to 32 years; this equated to 3.6 million person-years of follow-up.

Key findings:

Those in the highest quartile of a Western dietary pattern had a 31% increased CRC risk (RR=1.31) compared to those in the lowest quartile. In this context, a Western diet was characterized by consumption of red and processed meats, high-fat dairy products (such as whole milk), refined grains, and desserts.

The prudent diet cohort, had a 14% reduced risk for those in the highest quartile compared to the lowest quartile. The ‘prudent’ diet included high intakes of vegetables, fruits, whole grains, and fish.

Screening interval recommendations (Table 1): 10 years for no polyps or juvenile polyps in rectum/sigmoid.

Aspirin therapy may be beneficial but apply to persons who have no increased risk of bleeding and are willing to take low-dose aspirin (81 mg) daily. The greatest benefit is expected in persons 50 to 59 years and a potential benefit in 60 to 69 years of age.

Diets that are low in fat, regular physical exercise, maintenance of an appropriate body-mass index, and avoidance of smoking are recommended to lower risk.

“The USPSTF recommends initiating low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. (B recommendation)The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individual one.”

This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.